p21 as a transcriptional co-repressor of S-phase and mitotic control genes
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AuthorFerrándiz Díaz, Nuria; Caraballo Otero, Juan Manuel; García Gutiérrez, Lucía; Devgan, Vikram; Rodriguez Paredes, Manuel; Lafita Navarro, María Carmen; Bretones Sánchez, Gabriel; Quintanilla Cavia, Andrea; Muñoz Alonso, María José; Blanco Fernández, Rosa Fernanda; Reyes, José Carlos; Agell, Neus; Delgado Villar, María Dolores; Dotto, Gian Paolo; León Serrano, Javier
It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.
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